METHOD OF ENHANCING IMMUNE RESPONSE TO ORAL VACCINES

Abstract: The invention features a method of enhancing immune response to an oral vaccine of a recipient of the vaccine by administering, with the oral vaccine or close enough in time to bring about immune response enhancement, an immunoadjuvant comprising an effective amount of a strain of Lactobacillus bacteria that has the ability to colonize the intestinal tract of the recipient, preferably Lactobacillus Strain GG.

Description: METHOD OF ENHANCING IMMUNE RESPONSE TO ORAL VACCINES Background of the Invention The present invention relates to methods of enhancing immune response to oral vaccines. The development of oral vaccines offers great promise in the prevention of disease world-wide. Vaccines which successfully immunize after a single dose are preferred as they eliminate the problems associated with making sure that each subject receives the proper number of subsequent doses. However, some oral vaccines have inadequate immuno-genicity to ensure immunization with a single dose, particularly when administered to children. A number of chemical substances have been used as immunoadjuvants, i.e., substances that are administered with a vaccine to enhance cell-mediated immunity or to increase the humoral response to the immunogen used for vaccination. These substances have traditionally not been used with oral vaccines because they may cause undesirable side effects or are not suitable for oral administration. The term "immunoadjuvant", as used herein, refers to substances which enhance the immune response to a vaccine. Summary of the Invention The invention features a method of enhancing the immune response to an oral vaccine of a recipient of the vaccine. To enhance the immune response, an immunoadjuvant comprising an effective amount of a strain of Lactobacillus bacteria is administed to the recipient, with the oral vaccine or close enough in time to bring about immune response enhancement. Preferably, the Lactobacillus bacteria are able to survive at low pH and produce large amounts of an antimicrobial substance. Preferred strains having these properties are described in U.S. 4,839,281 and 5,032,399, the disclosures of which are incorporated herein by reference. Preferred bacteria are able to colonize the intestinal tract, as evidenced by the presence of the bacteria in the feces of the subject after oral administration, and preferably also have substantially the same properties exhibited by the Lactobacillus bacteria deposited in the American Type Culture Collection and given ATCC Accession No. 53103. Most preferably, the Lactobacillus bacteria is Lactobacillus Strain GG. In other preferred embodiments, the immunoadjuvant is administered in a pharmaceutically acceptable carrier, e.g., a fermented dairy product or a culture-containing powder, capsule or tablet. For optimal enhancement of the immune response, the Lactobacillus bacteria is preferably coadministered to the person given the vaccine, then administered alone to the person for a period of one or more days after administration of the vaccine. Advantageously, the immunoadjuvant of the invention enhances immunity after administration of an oral vaccine. The immunoadjuvant may allow immunity to be obtained from a single dose of an oral vaccine which, due to its characteristics or other factors, would otherwise require multiple doses, or may enhance the immune response to an oral vaccine. Alεo, as the Lactobacillus bacteria is a harmless naturally occurring substance, present in, e.g., yogurt, it produces no significant harmful side effects. Other features and advantages of the invention will be apparent from the description of the preferred embodiment thereof, and from the claims. Detailed Description of the Preferred Embodiment The term "Lactobacillus Strain GG" as used herein refers to a particular strain of Lactobacillus bacteria, a lactic acid bacteria. This strain is described in U.S. Patent Nos. 4,839,281 and 5,032,399, incorporated above by reference. The GG strain has been deposited in the American Type Culture Collection (ATCC) , Rockville, Mass., and has been given ATCC Accession No. 53103. Lactobacillus Strain GG may be cultured on any appropriate sterilized fermentation medium. When the Lactobacillus Strain GG is to be freeze-dried prior to addition to the vaccine, it is preferred that a cryoprotectant, e.g. monosodium glutarαate sodium ascorbate, saccharose or lactose, be added to the cells after culturing. The Lactobacillus Strain GG bacteria is administered in an amount which is sufficient to colonize the intestinal tract of the patient. A dosage of at least 10 8 cfu, preferably 10 8 to 10 10 cfu, is generally adequate for moεt patients. Dosages of 10 10 cfu are likely to completely colonize the intestinal tract of subεtantially all patientε. Higher dosages may be administered, if desired, but dosages above about 5xl0 10 cfu typically require impractically large volumes of the bacteria-containing material to be administered. It is preferred that the bacteria be administed to the patient over a εerieε of days, with the preferred dosage (above) given on each day. Preferably, the bacteria iε firεt coadministered with the vaccine, then administered alone for a period of 1 to 4 dayε, preferably 2 days, after adminiεtration of the vaccine. It haε been found that this courεe of treatment provides optimal enhancement of the immune response. The bac eria may be mixed with a pharmaceutically acceptable carrier or a food product, for ease of administration. For infants and small children, it is generally preferable to provide the bacteria in the form of a powder. For other patients, the bacteria may be provided in tablet or capsule form, as a freeze-dried powder which may be mixed with food or drink, or in any other suitable form. The bacteria may also be provided in the form of a actoJacillus-containing cultured dairy product, provided the product contains an effective amount of the bacteria. Oral vaccines which are suitable for use in the invention include, but are not limited to, vaccines for rotaviruε, typhoid, cholera, adenoviruε, polio, E. coli and the like. Preferred embodiments of the invention have been described herein. Other variations and modifications are within the scope of the invention and claims.

Claims: CLAIMS 1. A method of enhancing the immune response to an oral vaccine of a recipient of the vaccine comprising the step of administering, with the oral vaccine or close enough in time to bring about immune response enhancement, an immunoadjuvant comprising an effective amount of a strain of Lactobacillus bacteria that has the ability to colonize the intestinal tract of the recipient. 2. The method of claim 1 wherein the Lactobacillus bacteria is a strain in which the bacteria have substantially the same properties exhibited by the Lactobacillus bacteria deposited in the American Type Culture Collection and given ATCC Accession No. 53103. 3. The method of claim 2 wherein the Lactobacillus bacteria is Lactobacillus Strain GG. 4. The method of claim 1 wherein the immunoadjuvant is administered in a pharmaceutically acceptable carrier. 5. The method of claim 4 wherein the carrier is a fermented dairy product. 6. A method of claim 4 wherein the carrier is a culture-containing powder, capsule or tablet. 7. The method of claim 1 wherein the immunoadjuvant is coadministered to the patient with the vaccine, then administered alone to the patient for a period of one or more dayε after administration of the vaccine. 8. The method of claim 1 wherein the bacteria is administered in a dosage of at leaεt 10 8 cfu. 9. The method of claim 8 wherein each administration of the immunoadjuvant contains a dosage of at leaεt 10 8 cfu of the bacteria.

Inventors: GORBACH SHERWOOD L, ISOLAURI ERIKA, SALMINEN SEPPO J, GORBACH, SHERWOOD, L., ISOLAURI, ERIKA, SALMINEN, SEPPO, J.
Applicants: GORBACH SHERWOOD L, VALIO LTD, GORBACH, SHERWOOD, L., VALIO LTD.
Application year: 1994
Main classification: A61K37
IPC codes: A61K35, A61K39, C12N1